Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment

BACKGROUND: Enasidenib (IDHIFA(®), AG-221) is a first-in-class, targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia. This was a Phase I/II study evaluating safety, efficacy, and pharmacokinetics/pharmacodynamics (PK/PD) of orally administered enasidenib in subjects with advanced hematologic malignancies with an IDH2 mutation. METHODS: Blood samples for PK and PD assessment were collected. A semi-mechanistic nonlinear mixed effect PK/PD model was successfully developed to characterize enasidenib plasma PK and to assess enasidenib-induced CYP3A activity. RESULTS: The PK model showed that enasidenib plasma concentrations were adequately described by a one-compartment model with first-order absorption and elimination; the PD model showed a high capacity to induce CYP3A (E(max)=7.36) and a high enasidenib plasma concentration to produce half of maximum CYP3A induction (EC(50) =31,400 ng/mL). Monte Carlo simulations based on the final PK/PD model showed that at 100 mg once daily dose there was significant drug accumulation and a maximum of three-fold CYP3A induction after multiple doses. Although the EC(50) value for CYP3A induction by enasidenib is high, CYP3A induction was observed due to significant drug accumulation. CONCLUSION: CYP3A induction following enasidenib dosing should be considered when prescribing concomitant medication metabolized via this pathway.